Trauma is the leading cause of death in people under the age of 40 and MODS is the leading cause of death[unreadable] in intensive care units. Consequently, understanding the mechanisms by which trauma-hemorrhagic shock[unreadable] (T/HS) leads to MODS is of major health importance in this country. One of the major hypotheses being[unreadable] studied to explain the development of sepsis and MODS after trauma is the gut hypothesis of MODS.[unreadable] Additionally, there is recent experimental and clinical information that the response to injury and sepsis may[unreadable] differ between males and females. Thus, the overall global hypothesis of this grant is that trauma[unreadable] hemorrhagic (T/HS) shock-induced early distant organ injury and cellular dysfunction is secondary to gut[unreadable] injury and is primarily mediated by factors exiting the gut via the mesenteric lymphatics. Our secondary[unreadable] major hypothesis is that gender and sex hormones modulate gut and hence distant organ and cellular[unreadable] dysfunction after T/HS. These hypotheses are supported by our preliminary studies indicating that T/HSinduced[unreadable] lung injury and endothelial cell activation/dysfunction (Project by Deitch), neutrophil activation (Project by Hauser), red[unreadable] blood cell dysfunction (Project by MachiedoI) and bone marrow failure (Project by Kaiser) in male rats are mediated primarily by[unreadable] factors exiting the gut in the mesenteric lymph. Additionally, our studies show that proestrus female rats are[unreadable] resistant to these T/HS-induced injuries. Based on these results showing that female rats are more resistant[unreadable] to T/HS than male rats, the effects of gender and sex hormone modulation on cellular and organ dysfunction[unreadable] will be investigated. In all of the Projects, the mechanisms by which T/HS leads to these changes will be[unreadable] studied. Since T/HS-induced gut injury appears to be the initiating injury that induces this cascade of events,[unreadable] both Project by Deitch and Project by Feinman, will focus on determining the mechanisms by which T/HS leads to gut injury.[unreadable] Additionally, focused human studies in trauma patients will be carried out investigating trauma-induced[unreadable] neutrophil activation (Project by Hauser) and RBC dysfunction (Project by Machiedo). In summary, these projects will provide[unreadable] insight into the early mechanisms by which T/HS predisposes to MODS and will clarify the roles of gender[unreadable] and sex hormones as modulators of this response. The Administrative Core will serve to coordinate the[unreadable] activities of the various projects as well as be an information nexus, while the Animal Models Core will[unreadable] ensure consistency of the models being used and facilitate integration of the results obtained as well as[unreadable] reduce the costs of the overall proposal. The Human Core will serve to facilitate translational studies as well[unreadable] as aid in correlating the results of the human and animal studies. Lastly, Project by Kaiser focusing on factor[unreadable] isolation has been included to answer the question of what are the factors present in T/HS mesenteric lymph[unreadable] that are causing these changes in neutrophil, RBC and bone marrow function.